tbuckley/cabot-search huggingface dataset:
Screening for anxiety and depression in cancer patients using PHQ4.
Authors: Pooja N. Bhakta, Zachary E. Hunzeker, Sindusha R Gudipally, Maurice Willis, Rohit Venkatesan
Journal: Journal of Clinical Oncology (2022)

e18629 Background: The prevalence of anxiety and depression disorder in patients with cancer is about 10% and 22%, respectively. Cancer patients were seven times more likely to have a psychiatric disorder than the normal population. Prior studies have used multiple questionnaires like GAD7, HADS, PHQ2 and PHQ9 which have been approved by national guidelines to assess severity of anxiety and depression in the cancer population. Patient Health Questionnaire-4 (PHQ4) questionnaire is a validated screening tool for anxiety and depression disorders. This study aimed to implement a concise screening tool, PHQ4, to identify the mental health status of cancer patients early and intervene with counseling, medications, and referral to PCP/Palliative care for symptoms control. Methods: Patients completed the 4-item PHQ4 during their clinic visits at University of Texas Medical Branch between December 1, 2021, and February 1, 2022. The patient was provided with a PHQ4 questionnaire at the beginning of their visit. The PHQ4 implements two screening questions for anxiety and depression each, with the frequency of symptoms determining the score on a scale of 0 (not at all) to 3 (nearly every day) for each item. When the total score was &gt; or = 3, a presumptive diagnosis of anxiety, depression, or both was made. These patients were given information regarding support groups, resources for interventions, and provided with medications/referrals to primary care/palliative care/psychiatry for further management. Demographic factors (i.e., age, sex, race/ethnicity), type of cancer, and stage of cancer were other variables that were collected and analyzed as well. Results: Out of 70 total patients, 12 (17.1%) screened positive for anxiety, 14 (20%) screened positive for depression, and 9 (12.9%) screened positive for both depression and anxiety. 10 (14.3%) patients were diagnosed with mild symptoms (score 3-5), 10 (14.3%) with moderate symptoms (6-8), and 4 (5.7%) with severe symptoms. Median age of study population was 60, median age for positive screening was 54.5 years. While there were 35 males and females included in the study, 10 males (14.3%) and 7 females (10%) screened positive. Caucasian ethnicity (76.5%) and Colorectal cancer (24.3%) had the highest prevalence of patients who screened positive. All patients who screened positive were either stage 3 or 4 cancer patients. All patients (100%) who screened positive, received intervention. Conclusions: Based on our results, PHQ4 almost met the national average for depression screening. It possibly over diagnosed patients with anxiety and depression which may have been also contributed by other social/financial/personal stressors, warranting further attention with social worker support. PHQ4, is a quick, validated, effective screening tool that can regularly monitor cancer patients’ psychological health and enable timely intervention.
Preliminary results of a phase Ib/II combination study of RC48-ADC, a novel humanized anti-HER2 antibody-drug conjugate (ADC) with toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with locally advanced or metastatic urothelial carcinoma.
Authors: Xinan Sheng, Li Zhou, Zhisong He, Hongqian Guo, Xieqiao Yan, Siming Li, Huayan Xu, Juan Li, Zhihong Chi, Lu Si, Chuanliang Cui, Lili Mao, Bin Lian, Bixia Tang, Xuan Wang, Xue Bai, Jun Guo
Journal: Journal of Clinical Oncology (2022)

4518 Background: RC48-ADC has shown promising data in HER2-positive and even negative patients with metastatic urothelial carcinoma (mUC) who failed with platinum-based chemotherapy. RC48-ADC combined with anti-PD-1 antibody may have a synergistic antitumor effect. Methods: This is an open-label, multicenter, phase 1b/II trial to evaluate the safety and activity of RC48 combined with toripalimab in mUC. Patients received RC48-ADC at 1.5 or 2 mg/kg, in combination with 3mg/kg toripalimab every two weeks in a dose-escalation and expansion cohort until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The key primary endpoint was safety; secondary endpoints included efficacy and tumor tissue biomarkers. Results: As of 17 Jan 2022 (data cutoff), 41 la/mUC pts (19 males; median age 66 y [42-76]) were enrolled since 20 Aug 2020. 61% patients were systemic treatment naïve, and 54% had visceral metastases (mets), including 24% with liver mets. The primary site was in upper tract UC in 54%. HER2 expression was positive (IHC 2+ or 3+) in 59% patients, and PD-L1 positive (CPS ≥ 10) in 32%. No dose-limiting toxicity was observed. The recommended dose was RC48-ADC 2mg/kg + toripalimab 3mg/kg every 2 weeks. With a median follow-up of 8.0 mos, 36 patients had at least one tumor assessment, the best ORR was 83.3%, and the confirmed ORR was 76.7% (95%CI: 57.7, 90.1), including 10% CR. The cORR was 82.4% for 1L previously untreated mUC patients, 100% for patients with HER2 IHC (2+ or 3+) &amp; PD-L1 (+), 92.3% for HER2 (2+ or 3+) &amp; PD-L1 (-), 50% for HER2 (0 or 1+) &amp; PD-L1 (+), and 50% HER2 (0 or 1+) &amp; PD-L1 (-). DCR was 96.7% (95%CI: 82.8, 99.9). The median PFS was immature and 9.2 mos (95%CI: 5.49, 10.32) by the time and the median OS was not reached. The most common treatment-related AEs were ALT/AST increase (65.9%), peripheral sensory neuropathy (58.5%), appetite decrease (56.1%), asthenia (56.1%), hypertriglyceridemia (48.8%). Grade ≥3 TRAEs included γ-glutamyl transferase increase (12.2%), ALT/AST increase (7.3%), asthenia (7.3%), hypertriglyceridemia (4.9%), and neutropenia (4.9%). 9 pts had irAEs (22.0%, 7.3% ≥ G3), including immune-related pneumonitis, hepatitis, and myositis. Conclusions: RC48-ADC in combination with toripalimab demonstrated promising efficacy in patients with mUC and a manageable safety profile. A randomized study of RC48-ADC and toripalimab vs. platinum-based chemotherapy in previously untreated la/mUC patients is ongoing. Clinical trial information: NCT04264936. [Table: see text]
Anlotinib in combination with dose-intense temozolomide for the recurrent or progressive glioblastoma after STUPP regimen.
Authors: Qun-ying Yang, Cheng-cheng Guo, Yong-gao Mou
Journal: Journal of Clinical Oncology (2022)

e14014 Background: Nearly all patients (pts) with glioblastoma (GBM) will suffered relapse or disease progression after resection and adjuvant radiotherapy and temozolomide (TMZ). Anlotinib is a new multikinase inhibitors (MKI) blocking angiogenesis and tumor cell proliferation simultaneously and a prospective phase II study was performed to explore the potency of the combination anlotinib and TMZ for pts with relapse or progression GBM. Here, we reports the preliminary results of this study. Methods: This is a prospective, single-arm, open label, phase II study (NCT04547855). Eligible pts were diagnosed with histologically confirmed glioblastoma and experienced relapse or progression for the first time from surgery (including biopsy, partial resection and total resection) and radiotherapy-TMZ therapy (STUPP regimen). Other criteria included 18 to 75 years age, Karnofsky performance status (KPS) ≥ 60% and adequate organ function. The primary endpoint was progression free survival at 6 months (6m-PFS). All pts received orally TMZ (150 mg/m 2 ) from D1-D7 every 2 weeks and anlotinib (12mg, QD) from D1-D14 every 3 weeks until disease progression or unacceptable toxicities. Results: From July 2020 to November 2021, 25 pts were enrolled. The median age was 49 (rang: 23, 62) and the median KPS was 80 (range: 60, 100). Most pts had poor prognostic factors that 17 pts (70.8%) had unmethylated MGMT promoter and 22 pts (91.6%) were IDH wild-type, which 24 pts detected IDH and MGMT status. At the data cutoff date on January 2022, the 6m-PFS was 25.2% and the median PFS was 4.2 months (95% CI, 3.4-5.0m). The median OS reached 9.1 months (95% CI, 8.1-10.2). Tumor response was assessed for all pts. 7 pts achieved partial response and the objective response rate was 28%. 10 pts had stable disease and the disease control rate was 68%. The most common grade 3 or worse adverse events (AEs) was lympyhopenia (48.0%), which may be caused by TMZ. No death was attributed to AEs. Conclusions: Combination of anlotinib and dose-intense temozolomide was tolerable in the treatment of recurrent or progressive glioblastoma. Preliminary results indicated that the efficacy was promising for those miserable pts with worse prognosis factors. Further investigation was ongoing. Clinical trial information: NCT04547855.
Risk factors for cranial irradiation-related late neurocognitive toxicity: A prospective cohort study.
Authors: Debarati Bhanja, Kyle J. Tuohy, Hannah E. Wilding, Dawit Aregawi, Michael J. Glantz
Journal: Journal of Clinical Oncology (2022)

2066 Background: Neurocognitive dysfunction is a common complication of cranial irradiation, occurring in up to 50% of irradiated brain tumor patients. Symptoms often severely compromise quality of life long before patients succumb to their tumor; however, risk factors are poorly understood, and consequently, prognostication and prevention have not been possible. The objective of this study was to evaluate the prognostic value of vascular risk factors for the development of irradiation-related brain injury. Methods: This single-institution prospective cohort study included patients with malignant primary brain tumors who received cranial irradiation as part of their initial tumor-directed therapy. Three putative vascular risk factors – homocysteine, total cholesterol, apoprotein E genotype (ApOE) – were measured and dichotomized (above vs. below the laboratory normal). Univariate analyses compared each risk factor with four measures of neurocognitive dysfunction: mini-mental status exam (MMSE), MRI white matter changes at 6 months (MRI), physician (Phys) assessment, and patient (Pat) assessment. Decision analysis was used to construct a prediction algorithm. Results: 80 patients were included in this analysis. Elevated homocysteine was the most powerful and consistent predictor of neurocognitive toxicity, followed by elevated triglycerides and the ApOE genotype (Table). Logistic regression revealed a highly significant (p&lt;0.01) association between homocysteine level and each of the four outcome variables. Decision tree analysis using homocysteine level (high vs. low) and ApoE genotype (yes vs. no) provided the most efficient predictive algorithm. Conclusions: Two putative vascular risk factors (homocysteine level &gt; 14 and ApOE genotype) provide moderate ability to predict post-radiation neurocognitive dysfunction using a variety of simple but clinically meaningful definitions of dysfunction. This predictive algorithm should be validated in prospective trials. If these findings are corroborated, studies examining additional risk factors as well as studies looking at risk factor mitigation will be appropriate. [Table: see text]
The incidence of atrial fibrillation shortly following radiation therapy in patients with lung cancer: A population-based study.
Authors: Nikita Nikita, Bo Lu, Krupa Gandhi, Scott W. Keith, Grace L. Lu-Yao
Journal: Journal of Clinical Oncology (2022)

e18796 Background: Lung cancer is the third most common cause cancer in the US. Although radiation therapy (RT) is one of the most common treatment modalities for lung cancer. RT-induced atrial fibrillation (AFib) is understudied. We examined the relationship between different types of RT and AFib incidence. Methods: Lung cancer patients receiving RT were identified from the SEER-Medicare linked data between 2010 and 2015. Patients with 12 months continuous Part A and B coverage prior to RT were included. Patients were excluded if they lost coverage, were enrolled in HMOs, aged &lt; 65 years old, or diagnosed at death, had malignant effusion or pre-existing AFib. RT was identified as IMRT (HCPCS: 77301, 77418, G0174, G0178, 0073T), or non-IMRT related external beam radiation (HCPCS: 77290, 76370, 77014, 77295, 77280, 77285, CPT: 77402–77416, 77427). AFib was identified within 30 days of initiating RT using ICD-10 codes. Continuous variables were summarized by mean and standard deviation; categorical variables by frequency and percentage. Student’s t-test was used to compare continuous data between groups. Pearson’s chi-square test was used to compare categorical data between groups. Results: We identified 3,499 lung cancer patients receiving radiation. Of these, 830 were diagnosed with AFib after RT. The type of RT (IMRT vs non-IMRT) and type of hilar involvement were both associated with the incidence of AFib in these patients (Table). Conclusions: This is the first population based study to identify factors associated with increased AFib incidence in lung cancer patients receiving radiation. Further studies are warranted to better understand these associations.[Table: see text]
CORE1: Phase 2, single-arm study of CG0070 combined with pembrolizumab in patients with nonmuscle-invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guerin (BCG).
Authors: Roger Li, Gary D. Steinberg, Edward M. Uchio, Donald L. Lamm, Paras Shah, Ashish M. Kamat, Trinity Bivalacqua, Vignesh T. Packiam, Michael Jon Chisamore, John McAdory, Paola Grandi, Nataliya Hnat, James Burke
Journal: Journal of Clinical Oncology (2022)

4597 Background: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ̃20%. This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods: 35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x10 12 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction,viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: A CR rate of 87.5% (14/16) at the 3 m assessment timepoint has been observed thus far. All patients in CR at 3 m remain in CR at downstream timepoints including: 9/9 at 6 m, 6/6 at 9 m, and 3/3 at 12 m. Treatment related AE have been generally limited to transient grade 1-2 local-regional genitourinary adverse events with no reports of grade 3, 4 or SAE attributed to treatment with CG0070/Pembroluzimab. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. Additional data on efficacy as well as safety and biomarker (CAR, E2F, and PDL1) assessment will be presented for at least 25 of the projected 35 patients at the time of the conference. Clinical trial information: NCT04387461.
Increased systemic toxicities from antibody-drug conjugates (ADCs) with cleavable versus non-cleavable linkers: A meta-analysis of commercially available ADCs.
Authors: Carrie Wynn, Ritesh Patel, William B. Hillegass, Shou-Ching Tang
Journal: Journal of Clinical Oncology (2022)

3032 Background: Though in theory ADCs should deliver high-dose chemotherapy directly to target cells with few systemic effects, in clinical practice numerous side effects have been observed. We hypothesized that ADCs with cleavable linkers would have more systemic toxicities than those with non-cleavable linkers due to the increased free payload released systemically. To compare their side effect profiles, we conducted a meta-analysis of adverse events (AEs) of commercially available ADCs. Methods: Systematic review yielded 12 phase II/III clinical trials that led to the FDA approval of commercially available ADCs. Polatuzumab vedotin was not included because it was only studied in combination with other agents. Any grade AEs and grade ≥3 AEs occurring in at least 5% of patients in each study were recorded. The estimated inverse variance weighted absolute average risk and 95% confidence interval (CI) were estimated for each AE. Absolute risk differences and 95% CIs were estimated by linker type. Results: Data from 2,417 patients treated with 9 ADCs were pooled. 7 ADCs had cleavable linkers (N = 1,082), and 2 had non-cleavable linkers (N = 1,335). At least half of studies reported thrombocytopenia, neutropenia, anemia, increased AST and ALT, nausea, vomiting, diarrhea, hypokalemia, headache, and fatigue, as well as rates of all grade and grade ≥3 AEs. AEs ≥ grade 3 occurred in 43% of patients overall, 47% in the cleavable linker arms and 34% in the non-cleavable arms. This was significantly different (weighted risk difference -12.9%; 95% CI -17.1% to -8.8%). There was also a significant difference favoring non-cleavable linkers for ≥ grade 3 neutropenia (-9.1%; 95% CI -12% to -6.2%) and ≥ grade 3 anemia (-1.7%; 95% CI -3.3% to -0.1%). Cleavable linkers were significantly associated with increased AST all grade (3.9%; 95% CI 0.3% to 7.5%) and increased ALT all grade (3.7%; 95% CI 0.2% to 7.3%), though notably the CI approached 0 on the low end of difference for each. There was no significant difference in rates of all grade AEs or in rates of discontinuation due to AEs. There was no significant difference in rates of all grade nausea, vomiting, diarrhea, hypokalemia, or headache. Finally, there was no significant difference in rates of grade ≥3 thrombocytopenia, increased AST/ALT, or fatigue. Conclusions: Cleavable linkers appear to have significantly higher rates of ≥ grade 3 AEs and neutropenia within the limitations of this non-randomized comparison and treatment of heterogeneous malignancies. The increased payload in the circulation likely accounts for this; however, it may also make them more efficacious, as suggested by the results of the DESTINY-Breast03 trial. In the final analysis, we will compare the efficacy of cleavable vs non-cleavable ADCs indirectly using the standard of care for each tumor and line of therapy, with the exception of breast cancer.
Validation of a clinically relevant humanized mouse model for the safety assessment of 4-1BB agonists utomilumab and urelumab.
Authors: James G. Keck, Wenqian He, Bernard S. Buetow, Allison Vitsky, Maggie Liu, Jiwon Yang, Guoxiang Yang, Danying Cai, Bart Jessen
Journal: Journal of Clinical Oncology (2022)

e14602 Background: Immunotherapy is proven to be powerful and effective in treating cancer. One of the strategies for the therapy is to boost a patient’s immune system by stimulating tumor necrosis factor receptors via the activation of 4-1BB (CD137) costimulatory molecule. Urelumab was the first 4-1BB agonist investigated in clinical trials and showed clinical promise but doses were limited by severe liver toxicity. Preclinical assessment of toxicity failed to predict the clinical safety outcome. Methods: To address the critical needs of in vivo evaluation of toxicity in a preclinical setting, we have developed an animal model using PBMC humanized mice to assess the safety of immunotherapy. In this model, agents targeting human immune system including monoclonal and bispecific antibodies can induce an acute response of cytokine release within hours of treatment and with some therapies a systemic response can manifest in tissue damage and lethality of mice days later. Results: The potential clinical relevance of the PBMC humanized mouse model was demonstrated using 4-1BB agonists urelumab and utomilumab. The antibody-treated PBMC humanized mice were evaluated daily for clinical score and assessed for clinical chemistry and liver histopathology at study terminus. Animals dosed with urelumab at 10 mg/kg exhibited body weight loss and underwent early euthanasia, while animals dosed with utomilumab survived to scheduled euthanasia with minimum body weight loss. Urelumab showed marked liver toxicity relative to utomilumab and controls with more necrosis in the tissue and higher mean ALT, AST and GLDH activities, and the tolerability of urelumab was increased by lowering the dose to 1 mg/kg. The differences captured by the humanized mouse model presented a safety profile similar to the findings about urelumab and utomilumab from the clinical trials. Utomilumab was well tolerated at the dose that caused severe toxicity for urelumab in patients, and the toxicity of urelumab could be reduced by lowering the dose. Conclusions: Our data suggest that the PBMC humanized mouse model could identify human 4-1BB agonists that caused potentially severe liver toxicity. Preclinical safety assessment using humanized mouse models as used for these studies could be an important step in the course of the development of novel immunotherapy for the safety of patients as well as mitigating drug development cost.